Abstract
Malaria vaccine design and prioritization has been hindered by the lack of a mechanistic correlate of protection. We previously demonstrated a strong association between protection and merozoite-neutralizing antibody responses following vaccination of non-human primates against Plasmodium falciparum reticulocyte binding protein homolog 5 (PfRH5). Here, we test the mechanism of protection. Using mutant human IgG1 Fc regions engineered not to engage complement or FcR-dependent effector mechanisms, we produce merozoite-neutralizing and non-neutralizing anti-PfRH5 chimeric monoclonal antibodies (mAbs) and perform a passive transfer-P. falciparum challenge study in Aotus nancymaae monkeys. At the highest dose tested, 6/6 animals given the neutralizing PfRH5-binding mAb c2AC7 survive the challenge without treatment, compared to 0/6 animals given non-neutralizing PfRH5-binding mAb c4BA7 and 0/6 animals given an isotype control mAb. Our results address the controversy regarding whether merozoite-neutralizing antibody can cause protection against P. falciparum blood-stage infections, and highlight the quantitative challenge of achieving such protection.
Highlights
Malaria vaccine design and prioritization has been hindered by the lack of a mechanistic correlate of protection
Numerous immune effectors have been proposed as potential mediators of both naturally acquired and vaccine-induced protection against the P. falciparum blood-stage: merozoite neutralization independent of FcR bearing cells[1,2]; inhibition of parasite multiplication by soluble factors released by monocytes in response to merozoite binding by antibody, so-called antibody-dependent cellular inhibition (ADCI)[3]; neutrophil antibody-dependent respiratory burst activity upon encounter with opsonized merozoites[4]; merozoite phagocytosis by monocytes or neutrophils[5,6]; multiple effects of antibody binding to the infected erythrocyte surface[7]; and inhibition of blood-stage parasites by mechanisms orchestrated by CD4+ or CD8+ T cells[8,9]
We previously reported the isolation of a panel of murine monoclonal antibodies (mAbs) against PfRH518. 2AC7 is the most potent merozoite-neutralizing antiPfRH5 mAb of which we are aware: it recognizes a conformational epitope which has not been accurately mapped but, on the basis of competition binding experiments, is thought to be similar to that of 9AD4 at the apex of PfRH5’s kite-like structure18,19. 4BA7 is a non-neutralizing anti-PfRH5 mAb which binds a linear epitope in a disordered loop remote from the 9AD4 and basigin binding sites[18,19]
Summary
Malaria vaccine design and prioritization has been hindered by the lack of a mechanistic correlate of protection. Using mutant human IgG1 Fc regions engineered not to engage complement or FcR-dependent effector mechanisms, we produce merozoite-neutralizing and non-neutralizing anti-PfRH5 chimeric monoclonal antibodies (mAbs) and perform a passive transfer-P. falciparum challenge study in Aotus nancymaae monkeys. The best-standardized and most widely used tool for assessment of blood-stage vaccine-induced antibody functionality is the assay of growth inhibitory activity (GIA). This measures antibody-mediated P. falciparum merozoite neutralization in erythrocyte cultures lacking any FcR-bearing cells and without addition of complement[1]. We demonstrate that high levels of neutralizing antibodies can achieve protection This demonstration of a causal relationship between a defined immunological mechanism and protection may enable the use of GIA as a mechanistic correlate of protection[17] after vaccination of humans, facilitating future vaccine development
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